Nonhealing wounds in diabetes remain a global clinical and research challenge. Exosomes are primary mediators of cell paracrine action, which are shown to promote tissue repair and regeneration. In this study, we investigated the effects of serum derived exosomes (Serum‐Exos) on diabetic wound healing and its possible mechanisms. Serum‐Exos were isolated from blood serum of normal healthy mice and identified by transmission electron microscopy and western blot. The effects of Serum‐Exos on diabetic wound healing, fibroblast growth and migration, angiogenesis and extracellular matrix (ECM) formation were investigated. Our results showed that the isolated Serum‐Exos exhibited a sphere‐shaped morphology with a mean diameter at 150 nm, and expressed classical markers of exosomes including HSP70, TSG101, and CD63. Treatment with Serum‐Exos elevated the percentage of wound closure and shortened the time of healing in diabetic mice. Mechanistically, Serum‐Exos promoted granulation tissue formation and increased the expression of CD31, fibronectin and collagen‐ɑ in diabetic mice. Serum‐Exos also promoted the migration of NIH/3T3 cells, which was associated with increased expression levels of PCNA, Ki67, collagen‐α and fibronectin. In addition, Serum‐Exos enhanced tube formation in human umbilical vein endothelial cells and induced the expression of CD31 at both protein and messenger RNA levels. Collectively, our results suggest that Serum‐Exos may facilitate the wound healing in diabetic mice by promoting angiogenesis and ECM formation, and show the potential application in treating diabetic wounds.

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Delayed wound healing is a persistent medical problem mainly caused by decreased angiogenesis. Esculentin-1a(1-21)NH2 [Esc-1a(1-21)NH2], has broadspectrum antibacterial properties which comes from frog skins. It has shown promise as a treatment for wound healing. However, its effects on angiogenesis as well as the mechanism by which esc-1a(1-21)NH2 enhanced wound healing remained unclear. In this study, we analyzed the structural properties and biocompatibility of esc-1a(1-21)NH2 and evaluated its effect on wound closure using a full-thickness excision model in mice. Our results showed that esc-1a(1-21)NH2 significantly accelerated wound healing by increasing collagen deposition and angiogenesis, characterized by elevated expression levels of platelet, endothelial cell adhesion molecule-1 (CD31) and proliferating cell nuclear antigen (PCNA). Furthermore, the angiogenic activity of esc-1a(1-21)NH2 was confirmed in vitro by various assays. Esc-1a(1-21)NH2 significantly promoted cell migration and cell proliferation in human umbilical vein vascular endothelial cells (HUVECs) via activation of the PI3K/AKT pathway, and upregulated the expression of CD31 at both mRNA and protein levels. The effect of esc-1a(1-21)NH2 on angiogenesis was diminished by LY294002, a PI3K pathway inhibitor. Taken together, this study demonstrates that esc-1a(1-21)NH2 accelerates wound closure in mice by promoting angiogenesis via the PI3K/AKT signaling pathway, suggesting its effective application in the treatment of wound healing.